Plaque clearance is a better correlate of neural protection via passive amyloid immunization than soluble amyloid-beta (Aβ) clearance, and this protection is based on Fc receptor-mediated Aβ phagocytosis. These are the conclusions reported in the February 3 online PNAS, by Frederique Bard and colleagues at Elan Pharmaceuticals in South San Francisco, California, after a comparison of various Aβ antibody isotypes and their affinities for different epitopes of Aβ.

In the aftermath of Elan’s halted vaccination trial, these and other researchers have taken a step back to try to understand how Aβ pathology interacts with the immune system, and also to determine if passive immunization with antibodies to Aβ could become a safe and effective alternative to active immunization with Aβ peptide (see related ARF discussion and ARF related news story). In the present study, the researchers first compared antibodies directed against various epitopes of the Aβ1-42 peptide. They found that only antibodies that bind the N-terminal region were effective in binding plaques in unfixed brain tissue from PDAPP transgenic mouse brain or in triggering plaque clearance by phagocytosis in an ex-vivo assay (see ARF related news story and ARF related news story. Similar results were found in vivo. The authors report that plaque-binding correlated with clearance and neural protection, whereas the affinity of antibodies for soluble Aβ correlated less well with these measures of efficacy.

They also report that the isotype of the antibodies determined its efficacy in plaque clearance and neuronal protection; IgG2a antibodies were more effective than IgG1 or IgG2b. IgG2a has a much higher affinity for the phagocytic Fc receptors, and the authors conclude that antibody efficacy is primarily mediated by Fc receptors and not by complement system receptors.—Hakon Heimer

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  1. The immunological concept in the treatment of conformational diseases, such as Alzheimer’s, is based on antibody-antigen interactions involving conformational changes in both antibody and antigen. Appropriate mAbs interact at strategic sites where protein aggregation is initiated, stabilize the protein and prevent further aggregation. For such an active role, the mAbs require a high binding constant to the "strategic" positions on the antigen molecule (Solomon, 2002). The existence of strategic positions where conformational changes are initiated has been shown in model systems (Silen et al., 1989; Solomon et al., 1995), recently in Alzheimer’s Aβ peptide (Frenkel et al., 1998; Frenkel et al., 1999) and prion-related diseases (Peretz et al., 2001; Hanan et al., 2001). The many authors of the Bard et al. paper show in a most convincing way that antibodies against the N-terminus of Aβ are effective in clearing amyloid plaques (Hanan et al., 1996; Solomon et al., 1997), thus partially avoiding the drawbacks related to immunization with whole Aβ1-42. At the same time, the study lacks the rationale regarding the minimal epitope of anti-aggregating antibodies.

    Using a phage-peptide library composed of filamentous phage displaying three million random combinatorial peptides, we defined the EFRH residues located at positions 3-6 of the N-terminal Aβ as the epitope of anti-aggregating antibodies within Aβ (Frenkel et al., 1998; Frenkel et al., 1999). The EFRH is not only the epitope of anti-aggregating antibodies but acts as a regulatory site controlling both the formation and disaggregation process of the amyloid fibrils. Locking of this epitope by highly specific antibodies affects the dynamics of the entire Aβ molecule, preventing self-aggregation as well as enabling resolubilization of already formed aggregates. This conclusion was reached from experimental data with different lengths of Aβ peptides or similar peptides with one or two mutations in EFRH region (Frenkel et al., 1998; Frenkel et al., 1999).

    Antibodies resulting from EFRH immunization are similar in their anti-aggregating properties to antibodies raised by direct injection with whole Aβ and/or mAbs directed to this region (Frenkel et al., 2000). Such antibodies at low titer (1-100—1-1000) are enough to reduce the amyloid plaques to the same extent as passive immunization with larger amounts of antibodies directed to EFRH (Frenkel et al., 2003). Antibodies that bind to the epitope containing only a few amino acids from EFRH, such as mAb 3D6 (Bacskai et al., 2002), are less effective compared to mAb 10D5, which binds to the whole sequence.

    However, not all the antibodies that bind to EFRH exhibit anti-aggregating properties. Mab 2H3, whose epitope is located between amino acids 1-7, binds with a higher binding constant (10-9M) to the whole epitope, but only with (10-4M) to EFRH and did not have anti-aggregating properties, highlighting the importance of the high affinity of the antibodies to this specific sequence on the behavior of whole Aβ (Frenkel et al., 1999).

    Unfortunately, immunization could have contradictory effects; besides disaggregating amyloid plaques it could trigger also microglial overactivation, which might lead to neuroinflammation. Mabs that bind to available epitopes of Aβ in brain (passive or active immunization) activate the Fc receptors which may initiate the inflammatory response. Modulation of FcR activation, using antibodies devoid of the Fc region, or partial FcR blockage, may be efficient practical therapeutic approaches for controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD (Solomon, 2002).

    References:

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    . The alpha-lytic protease pro-region does not require a physical linkage to activate the protease domain in vivo. Nature. 1989 Oct 5;341(6241):462-4. PubMed.

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    . N-terminal EFRH sequence of Alzheimer's beta-amyloid peptide represents the epitope of its anti-aggregating antibodies. J Neuroimmunol. 1998 Aug 1;88(1-2):85-90. PubMed.

    . High affinity binding of monoclonal antibodies to the sequential epitope EFRH of beta-amyloid peptide is essential for modulation of fibrillar aggregation. J Neuroimmunol. 1999 Mar 1;95(1-2):136-42. PubMed.

    . Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. 2001 Aug 16;412(6848):739-43. PubMed.

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    . Protective effect of monoclonal antibodies against Alzheimer’s beta-amyloid aggregation. Amyloid: Int. J. Exp. Clin. Invest. 1996;3:130-133

    . Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4109-12. PubMed.

    . Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci. 2002 Sep 15;22(18):7873-8. PubMed.

    . Immunization against Alzheimer's beta -amyloid plaques via EFRH phage administration. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11455-9. PubMed.

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  2. This is a study on a quite impressive scale that compares different isotypes of anti-Abeta antibodies with respect to efficacy in attenuating amyloid loads in PDAPP mice. The conclusion is anti-Abeta IgG with high affinity for Fc receptors are more effective then those with lower affinity for FcR. This supports this group's hypothesis that microglial uptake of anti-Abeta:Abeta complexes is important in Abeta immunotherapy. Our group is currently preparing a manuscript that is not easily reconcilable with these findings. Our data has also been presented at recent meetings. We find that Abeta immunotherapy is equally effective in Tg2576 mice crossed into an FcR gamma knockout background mice as it is in wt Tg2576 mice. Our studies would seem to preclude FcR mediated uptake of anti-Abeta:Abeta complexes as a factor in determing efficacy of immunization. Although there was no good correlation between efficacy in the bard study and binding affinites of the antibodies to soluble or aggregated Abeta, perhaps there is some other property of the anibodies that is more closely associated with efficacy? For example binding to oligomers, ability to cross the blood brain barrier, etc....

    View all comments by Todd E. Golde

References

News Citations

  1. The Alzheimer's Vaccination Story, Continued
  2. A Kinder, Gentler Alzheimer's Vaccine?
  3. Early-Stage Alternative Vaccine Reported: Better Antibody Response with Liposomes?

Other Citations

  1. related ARF discussion

Further Reading

Primary Papers

  1. . Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2023-8. Epub 2003 Feb 3 PubMed.